Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>C(C(C)=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1
Yield: 88.2 %

Procedure:
18.3 g of p-hydroxybenzaldehyde is dissolved in 200 ml of methyl ethyl ketone, and then 22.8 g of potassium carbonate and 24.2 g of m-chlorobenzyl chloride are added thereto. The resulting mixture is refluxed for 8 hours in a stream of nitrogen. Insoluble substances produced are removed by filtration, and then the solvent is distilled away. The resulting residue is distilled under reduced pressure to obtain 32.6 g of 4-(3-chlorobenzyloxy)benzaldehyde in the form of white crystal.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-].[Na+:18].O>CO>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:18].[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water in Methanol]. The reaction mixture was heated to reflux temperature for 22 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2×50 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (84%) of Zoledronate trisodium crystal form XI in a mixture with crystal form IX (LOD by TGA=10.5%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[C:11](=[O:14])([O-:13])[O-].[Na+].[Na+].F[C:18](F)(F)[C:19]([O:21][C:22](=O)[C:23](F)(F)F)=[O:20].O>CCOCC>[C:19]([OH:21])(=[O:20])/[CH:18]=[CH:2]/[C:11]([OH:13])=[O:14].[F:9][C:7]1[CH:8]=[CH:2][C:3]2[N:4]([NH:4][CH:3]([CH3:5])[CH3:2])[C:6]3[CH2:7][CH2:8][CH2:22][C:23]=3[C:5]=2[C:6]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1cc(F)c(F)cc1Br
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Nn1c2c(c3c(F)c(F)ccc31)CCC2
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 238.4 %

Procedure:
To a stirred solution of 2-bromo-4,5-difluoroaniline [H. Ishikawa, T. Uno, H, Miyamoto, H. Hiraki, H. Tamaoka, M. Tominaga and K. Nakagawa, Chem. Pharm. Bull., 1990, 38(9), 2459-2462] (72 g, 34 mmol) in ether (50 mL) at 0° C. was added sodium carbonate (5.4 g, 44 mmol) and trifluoroacetic anhydride (6.2 mL, 44 mmol). The reaction mixture was stirred at room temperature for 1 h. Water (100 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to give the product (9.9 g, 94%) as a white solid. IR νmax (Nujol)/cm−1 3270, 1716, 1550, 1489, 1465, 1226, 1181, 919, 876 and 821; NMR δH (400 MHz, CDCl3) 7.45-7.5 (1H, dd, J 7.5 Hz), 8.28-8.34 (1H, dd, J 8 Hz) and 8.36 (1H, br s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].C(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>O>[Cl:13][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: ClC(Cl)Cl
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1nccc2ccccc12
Reaction time: 3 h
Yield: 44.9 %

Procedure:
69.3 g (448 mmol) of isoquinoline N-oxide (made by Tokyo Kasei) and 225 ml of chloroform were placed and dissolved in a 1 liter-three-necked flask, and under stirring and cooling with ice, 219.6 g (1432 mmol) of phosphorus oxychloride was gradually added dropwise thereto while the internal temperature was held at 15-20° C. Thereafter, the temperature was raised, and reflux under stirring was performed for 3 hours. The reaction product was cooled by standing to room temperature and poured into iced water. After extraction with ethyl acetate, the organic layer washed with water until neutrality, and the solvent was removed under a reduced pressure to provide a dry solid, which was then purified by silica gel column chromatography (eluent: chloroform/hexane=5/1) to obtain 35.5 g (yield: 44.9%) of 1-chloroisoquinoline white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15](Cl)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].N.O>C1COCC1>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:15]2[C:9]3[CH:8]=[N:7][C:6]([NH:5][CH2:4][C:3]4[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=4[Cl:1])=[N:11][C:10]=3[CH:12]=[CH:13][N:14]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Clc1ccccc1CNc1ncc2c(Cl)nccc2n1
Reactant: CCOC(=O)C1CCNCC1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
(2-Chloro-benzyl)-(5-chloro-pyrido[4,3-d]pyrimidin-2-yl)-amine 9 (500 mg, 1.64 mmol), Piperidine-4-carboxylic acid ethyl ester 12 (0.51 mL, 3.28 mmol) and NH3 (25% solution in water, 0.22 mL, 3.28 mmol) were dissolved in THF (5 mL) and stirred at 100° C. in a high pressure flask for 15 hours. To the mixture water (5 mL) was added and the precipitate formed was filtered off and dried in vacuo. The obtained colorless solid (583 mg, 1.37 mmol, 84%) was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](I)[N:6]=1)=[O:4].[CH2:25]([OH:28])[C:26]#[CH:27].CN(C=O)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([C:27]#[C:26][CH2:25][OH:28])[N:6]=1)=[O:4]
Reactant: C#CCO
Reactant: COC(=O)c1nc(I)c2cccnc2c1OC(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#CCO)c2cccnc2c1OC(=O)c1ccccc1

Procedure:
A mixture of 5-iodo-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (2.00 g, 4.61 mmol), propargyl alcohol (0.563 mL, 9.67 mmol), dichlorobis(triphenylphosphine)palladium(II) (65 mg, 0.092 mmol), and copper iodide (4 mg, 0.023 mmol) were stirred in triethylamine (13 mL) and dry DMF (5 mL) at 30° C. overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (50-100% EtOAc/Hexane gradient elution switching to 5% MeOH/CH2Cl2) to provide the desired product was a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:36]([O:40][CH:41]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])[C@H:42]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])[NH2:43])[CH2:37][CH2:38][CH3:39]>CN(C)C=O.C(N(CC)CC)C>[CH2:52]([O:51][CH:41]([O:40][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:42]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])[NH:43][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:53][CH2:54][CH3:55]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCOC(OCCCC)[C@@H](N)CCCNC(=N)N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
In 25 ml of dimethylformamide was dissolved 2.65 g of N-benzyloxycarbonyl-L-leucine. After cooling to -15° C., 1.10 ml of N-methylmorpholine and then 1.37 ml of isobutyl chloroformate were added to the solution while stirring the solution at the same temperature. The mixture was sitrred at -15° C. for 5 minutes. On the other hand, 3.25 g of L-argininal dibutyl acetal hydrochloride (Example 2) was dissolved in 30 ml of dimethylformamide and 1.40 ml of triethylamine was added to the solution. The resulting solution was dropwise added at -10° C. to the mixed acid anhydride suspension which had been previously prepared. Stirring was continued at the same temperature for an hour and then at 0° C. for an hour. The resulting reaction solution was concentrated under reduced pressure and the residue was dissolved in 100 ml of chloroform. The solution was washed successively with 10% citric acid aqueous solution (30 ml×2), saturated sodium chloride aqueous solution (30 ml×1), saturated sodium hydrogencarbonate aqueous solution (30 ml×2) and saturated sodium chloride aqueous solution (30 ml×2). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel as a carrier and developed with chloroform: methanol=20:1 (v/v). The fraction showing Rf: 0.48 (under the same conditions as in Example 1 (A) 4) which was positive in the Sakaguchi reaction, was concentrated under reduced pressure to give 3.73 g of N-benzyloxycarbonyl-L-leucyl-L-argininal dibutyl acetal.
Reaction SMILES: N1C=CC(C2N([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)N=CN=2)=CC=1.[N:30]1[C:39]2C(=CC=CC=2)C=C[C:31]=1COC1C=CC(C(N)=O)=CC=1.[N:51]1[CH:56]=[CH:55][C:54]([NH:57][NH2:58])=[CH:53][CH:52]=1>>[N:51]1[CH:56]=[CH:55][C:54]([N:57]2[C:39]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:28][CH:29]=3)=[N:30][CH:31]=[N:58]2)=[CH:53][CH:52]=1
Reactant: NNc1ccncc1
Reactant: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Reactant: NC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: c1ccc2nc(COc3ccc(-c4ncnn4-c4ccncc4)cc3)ccc2c1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline but substituting 4-(Quinolin-2-ylmethoxy)-benzamide and Pyridin-4-yl-hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=6.2 Hz, 2 H), 8.21 (d, J=8.3 Hz, 1 H), 8.08 (s, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (m, 1 H), 7.65 (d, J=8.7 Hz, 1 H), 7.55 (m, 1 H), 7.43 (d, J=9.1 Hz, 2H), 7.32 (d, J=6.2 Hz, 2 H), 7.05 (d, J=8.7Hz, 2H), 5.40 (s, 2H); MS: (M+H m/z=380.2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][N:32]([CH3:35])[C:31](=[O:36])[CH:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]([CH3:35])[C:31](=[O:36])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.16, m/z=921.5; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1H), 1.52 (m, 3H), 2.21 (s, 2H), 2.22-2.34 (m, 2H), 2.34-2.46 (m, 1H), 2.85 (m, 1H), 3.57 (s, 3H), 5.59 (m, 1H), 6.33 (d, 1H), 6.68 (s, 1H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); 1H NMR (CD3OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.50 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.59 (m, 1H), 6.61 (d, 1H), 6.66 (s, 1H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][NH:40][CH3:41]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:40]([CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[CH3:41])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CNCCN(C)C
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N(C)CCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 97.7 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (0.026 mL, 0.20 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (21 mg, 97%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 2.11 (s, 6H), 2.37 (s, 3H), 2.41 (m, 2H), 3.02 (m, 3H), 3.50 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.16 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[O:11]1[C:15]2([CH2:20][CH2:19][CH:18](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.[OH-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]1[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc2c(ccn2C2CCC3(CC2)OCCO3)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 19.9 %

Procedure:
A mixture of 5-bromoindole (8.472 g, 43.216 mmol), toluene-4-sulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (13.5 g, 43.216 mmol) (prepared according to the procedure described in Journal of the Chemical Society, Perkin Transactions 1 (2002), (20), 2251-2255) and powdered potassium hydroxide (13.239 g, 235.958 mmol) in DMSO (300 ml) was stirred at 80° C. for 6 h. Subsequently, the mixture was cooled to room temperature and poured into ice water. The resulting aqueous mixture was extracted with Et2O, dried (Na2SO4), and the volatiles were evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM/heptane 1:1 as eluent). The desired fractions were collected and evaporated in vacuo to yield D29 (2.897 g, 19.93%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:3]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:18][C:16]([CH3:19])([CH3:17])[CH2:15][O:14][C:4]1[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([NH2:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)COc1cc(N)nc(N2CCOCC2)n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(COc1cc(N)nc(N2CCOCC2)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 34.4 %

Procedure:
1-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol (1.03 g; 3.8 mmol) and imidazole (500 mg; 8 mmol) were-dissolved in dimethyl formamide (16 mL). To this solution was added tert-butyldimethylsilyl chloride (1.2 g; 8 mmol), and it was stirred for 72 hours. The solution was poured into ethyl acetate (100 mL) which was then washed with water (3×200 mL). The organic layer was separated, dried over magnesium sulfate, and purified by column chromatography to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-2-methyl-propoxy]-2-morpholin-4-yl-pyrimidin-4-ylamine (500 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35]>>[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:34](=[O:35])[C:33]1[CH:37]=[C:29]([Br:28])[CH:30]=[CH:31][C:32]=1[NH2:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Yield: 107.9 %

Procedure:
(S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (1.53 g) was prepared from (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester HCl salt (1.0 g, 2.6 mmol) and 5-bromo-2-amino-benzoic acid (0.5 g, 2.9 mmol) as described in general procedure A.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])(C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:37])=[O:46])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoic acid (345 mg, 0.86 mmol) in methylene chloride (10 mL) are added triethyl amine (0.36 mL, 2.58 mmol), DMAP (5.0 mg), 3-amino-propionic acid tert-butyl ester (468.2 mg, 2.58 mmol) and EDCI (495.6 mg, 2.58 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoylamino)-propionoate (400 mg).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([OH:29])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:3])[CH3:2].[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([O:29][C:42](=[O:45])[CH2:43][CH3:44])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)O[C@H]1[C@@](C)(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@]1(F)COc1ccc2ccccc2c1O[P+]([O-])=N[C@@H](C)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
To a solution of (S)-2-[[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester prepared in Example 2 (86 mg, 144 μmol) in THF (10 mL) were added propionyl chloride (66.6 mg, 720 μmol) and DMAP (87.9 mg, 720 μmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 0-15% MeOH in DCM) to give the title compound as white solid (45 mg, 48%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[C:34]2[N:33]=[CH:32][CH:31]=[N:30][C:29]=2[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:19]4[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=4[CH3:17])=[CH:26][CH:27]=3)=[O:36])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2nc(CN3CCN(C)CC3)c[nH]2)c2nccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for at 60° C. overnight, using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3 and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71), and using Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 456.1 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[O:3]1.CO>[Pd].C1C=CC=CC=1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:2]2([CH3:1])[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][C:8]=3[CH3:12])[O:3]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c2c(c1)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(N)cc1)CC2
Yield: 75 %

Procedure:
Following a procedure similar to that described in Preparation 4, 2.1 g of 2,5,7-trimethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 25) were hydrogenated at atmospheric pressure, using 200 mg of 10% w/w/ palladium-on-carbon, 20 ml of methanol and 50 ml of benzene, to afford 1.44 g of the title compound.